Physical Biology of the Cell

Rob Phillips, Jane Kondev and Julie Theriot

April 4, 2008

Contents
0.1

Preface

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Facts of Life

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1 Why: Biology By the Numbers

1.1 Physical Biology of the Cell . . . . . . . . . . . . . . .
1.2 The Stuff of Life . . . . . . . . . . . . . . . . . . . . .
1.3 Model Building in Biology . . . . . . . . . . . . . . . .
1.3.1 Models as Idealizations . . . . . . . . . . . . .
1.3.2 Cartoons and Models . . . . . . . . . . . . . .
1.4 Quantitative Models and the Power of Idealization . .
1.4.1 On the Springiness of Stuff . . . . . . . . . . .
1.4.2 The Toolbox of Fundamental Physical Models .
1.4.3 The Role of Estimates . . . . . . . . . . . . . .
1.4.4 On Being Wrong . . . . . . . . . . . . . . . . .
1.4.5 Rules of Thumb: Biology by the Numbers . . .
1.5 Summary and Conclusions . . . . . . . . . . . . . . . .
1.6 Further Reading . . . . . . . . . . . . . . . . . . . . .
1.7 References . . . . . . . . . . . . . . . . . . . . . . . . .

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2 What and Where: Construction Plans for Cells and Organisms

2.1 An Ode to E. coli . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1 The Bacterial Standard Ruler . . . . . . . . . . . . . . . .
2.1.2 Taking the Molecular Census . . . . . . . . . . . . . . . .
2.1.3 Looking Inside of Cells . . . . . . . . . . . . . . . . . . . .
2.1.4 Where Does E. coli Fit? . . . . . . . . . . . . . . . . . . .
2.2 Cells and Structures Within Them . . . . . . . . . . . . . . . . .
2.2.1 Cells: A Rogues Gallery . . . . . . . . . . . . . . . . . . .
2.2.2 The Cellular Interior: Organelles . . . . . . . . . . . . . .
2.2.3 Macromolecular Assemblies: The Whole is Greater than
the Sum of the Parts . . . . . . . . . . . . . . . . . . . . .
2.2.4 Viruses as Assemblies . . . . . . . . . . . . . . . . . . . .
2.2.5 The Molecular Architecture of Cells: From PDB Files to
Ribbon Diagrams . . . . . . . . . . . . . . . . . . . . . . .
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CONTENTS
2.3

2.4
2.5
2.6
2.7

Telescoping Up in Scale: Cells Dont Go It Alone . . . . . . . .

2.3.1 Multicellularity As One of Evolutions Great Inventions
2.3.2 Cellular Structures From Tissues to Nerve Networks . .
2.3.3 Multicellular Organisms . . . . . . . . . . . . . . . . . .
Summary and Conclusions . . . . . . . . . . . . . . . . . . . . .
Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 When: Stopwatches at Many Scales

3.1 The Hierarchy of Temporal Scales . . . . . . . . . . . . . .
3.1.1 The Pageant of Biological Processes . . . . . . . . .
3.1.2 The Evolutionary Stopwatch . . . . . . . . . . . . .
3.1.3 The Cell Cycle and the Standard Clock . . . . . . .
3.1.4 Three Views of Time in Biology . . . . . . . . . . .
3.2 Procedural Time . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1 The Machines (or Processes) of the Central Dogma .
3.2.2 Clocks and Oscillators . . . . . . . . . . . . . . . . .
3.3 Relative Time . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.1 Checkpoints and the Cell Cycle . . . . . . . . . . . .
3.3.2 Measuring Relative Time . . . . . . . . . . . . . . .
3.3.3 Killing the Cell: The Life Cycles of Viruses . . . . .
3.3.4 The Process of Development . . . . . . . . . . . . .
3.4 Manipulated Time . . . . . . . . . . . . . . . . . . . . . . .
3.4.1 Chemical Kinetics and Enzyme Turnover . . . . . .
3.4.2 Beating the Diffusive Speed Limit . . . . . . . . . .
3.4.3 Beating the Replication Limit . . . . . . . . . . . . .
3.4.4 Eggs and Spores: Planning for the Next Generation
3.5 Summary and Conclusions . . . . . . . . . . . . . . . . . . .
3.6 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7 Further Reading . . . . . . . . . . . . . . . . . . . . . . . .
3.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4 Who: Bless the Little Beasties

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4.1 Choosing a Grain of Sand . . . . . . . . . . . . . . . . . . . . . . 175
4.1.1 Biochemistry and Genetics . . . . . . . . . . . . . . . . . 177
4.2 Hemoglobin as a Model Protein . . . . . . . . . . . . . . . . . . . 180
4.2.1 Hemoglobin, Receptor-Ligand Binding and the Other Bohr 182
4.2.2 Hemoglobin and the Origins of Structural Biology . . . . 184
4.2.3 Hemoglobin and Molecular Models of Disease . . . . . . . 188
4.2.4 The Rise of Allostery and Cooperativity . . . . . . . . . . 188
4.3 Bacteriophage and Molecular Biology . . . . . . . . . . . . . . . 189
4.3.1 Bacteriophage and the Origins of Molecular Biology . . . 190
4.3.2 Bacteriophage and Modern Biophysics . . . . . . . . . . . 195
4.4 A Tale of Two Cells: E. Coli as a Model System . . . . . . . . . 199
4.4.1 Bacteria and Molecular Biology . . . . . . . . . . . . . . . 199

CONTENTS

4.4.2 E. coli and The Central Dogma . . . . . . . . . . . . . . . 199

4.4.3 The lac Operon as the Hydrogen Atom of Genetic Circuits202
4.4.4 Signaling and Motility: The Case of Bacterial Chemotaxis 205
4.5 Yeast: From Biochemistry to the Cell Cycle . . . . . . . . . . . . 207
4.5.1 Yeast and the Rise of Biochemistry . . . . . . . . . . . . . 208
4.5.2 Dissecting the Cell Cycle . . . . . . . . . . . . . . . . . . 209
4.5.3 Deciding Which Way is Up: Yeast and Polarity . . . . . . 209
4.5.4 Dissecting Membrane Traffic . . . . . . . . . . . . . . . . 212
4.5.5 Genomics and Proteomics . . . . . . . . . . . . . . . . . . 215
4.6 Flies and Modern Biology . . . . . . . . . . . . . . . . . . . . . . 218
4.6.1 Flies and the Rise of Modern Genetics . . . . . . . . . . . 218
4.6.2 How the Fly Got His Stripes . . . . . . . . . . . . . . . . 220
4.7 Of Mice and Men . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
4.8 The Case for Exotica . . . . . . . . . . . . . . . . . . . . . . . . . 223
4.8.1 Specialists and Experts . . . . . . . . . . . . . . . . . . . 224
4.8.2 The Squid Giant Axon and Biological Electricity . . . . . 225
4.8.3 Exotica Toolkit . . . . . . . . . . . . . . . . . . . . . . . . 228
4.9 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . 229
4.10 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
4.11 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
4.12 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

II

Life at Rest

5 Mechanical and Chemical Equilibrium in the Living Cell

5.1 Energy and the Life of Cells . . . . . . . . . . . . . . . . . . . . .
5.1.1 The Interplay of Deterministic and Thermal Forces . . . .
5.1.2 Constructing the Cell: Managing the Mass and Energy
Budget of the Cell . . . . . . . . . . . . . . . . . . . . . .
5.2 Biological Systems as Minimizers . . . . . . . . . . . . . . . . . .
5.2.1 Equilibrium Models for Out of Equilibrium Systems . . .
5.2.2 Proteins in Equilibrium . . . . . . . . . . . . . . . . . .
5.2.3 Cells in Equilibrium . . . . . . . . . . . . . . . . . . . .
5.2.4 Mechanical Equilibrium From a Minimization Perspective
5.3 The Mathematics of Superlatives . . . . . . . . . . . . . . . . . .
5.3.1 The Mathematization of Judgement: Functions and Functionals . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.2 The Calculus of Superlatives . . . . . . . . . . . . . . . .
5.4 Configurational Energy . . . . . . . . . . . . . . . . . . . . . . .
5.4.1 Hookes Law: Actin to Lipids . . . . . . . . . . . . . . . .
5.5 Structures as Free Energy Minimizers . . . . . . . . . . . . . . .
5.5.1 Entropy and Hydrophobicity . . . . . . . . . . . . . . . .
5.5.2 Gibbs and the Calculus of Equilibrium . . . . . . . . . . .
5.5.3 Structure as a Competition . . . . . . . . . . . . . . . . .
5.5.4 An Ode to G . . . . . . . . . . . . . . . . . . . . . . . .

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CONTENTS
5.6
5.7
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Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . 291

Appendix: The Euler-Lagrange Equations, Finding the Superlative292
Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

6 Entropy Rules!
301
6.1 The Analytical Engine of Statistical Mechanics . . . . . . . . . . 301
6.1.1 A First Look at Ligand-Receptor Binding . . . . . . . . . 307
6.1.2 The Statistical Mechanics of Gene Expression: RNA Polymerase and the Promoter . . . . . . . . . . . . . . . . . . 312
6.1.3 Classic Derivation of the Boltzmann Distribution . . . . . 318
6.1.4 Boltzmann Distribution by Counting . . . . . . . . . . . . 321
6.1.5 Boltzmann Distribution by Guessing . . . . . . . . . . . . 325
6.2 On Being Ideal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
6.2.1 Average Energy of a Molecule in a Gas . . . . . . . . . . 332
6.2.2 Free Energy of Dilute Solutions . . . . . . . . . . . . . . . 335
6.2.3 Osmotic Pressure as an Entropic Spring . . . . . . . . . . 337
6.3 The Calculus of Equilibrium Applied: Law of Mass Action . . . . 341
6.3.1 Law of Mass Action and Equilibrium Constants . . . . . . 343
6.4 Applications of the Calculus of Equilibrium . . . . . . . . . . . . 345
6.4.1 A Second Look at Ligand-Receptor Binding . . . . . . . . 345
6.4.2 Measuring Ligand-Receptor Binding . . . . . . . . . . . . 347
6.4.3 Beyond Simple Ligand-Receptor Binding: The Hill Function347
6.4.4 ATP Power . . . . . . . . . . . . . . . . . . . . . . . . . . 350
6.5 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . 352
6.6 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
6.7 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
6.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
7 Two-State Systems: From Ion Channels to Cooperative Bind357
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7.1 Macromolecules With Multiple States . . . . . . . . . . . . . . . 358
7.1.1 The Internal State Variable Idea . . . . . . . . . . . . . . 358
7.1.2 Ion Channels as an Example of Internal State Variables . 361
7.2 State Variable Description of Binding . . . . . . . . . . . . . . . 366
7.2.1 The Gibbs Distribution: Contact with a Particle Reservoir 367
7.2.2 Simple Ligand-Receptor Binding Revisited . . . . . . . . 369
7.2.3 Phosphorylation as an Example of Two Internal State
Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
7.2.4 Hemoglobin as a Case Study in Cooperativity . . . . . . . 375
7.3 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . 386
7.4 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
7.5 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
7.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

CONTENTS

8 Random Walks and the Structure of Macromolecules

8.1 What is a Structure: PDB or RG ? . . . . . . . . . . . . . . . .
8.1.1 Deterministic vs. Statistical Descriptions of Structure .
8.2 Macromolecules as Random Walks . . . . . . . . . . . . . . . .
8.2.1 A Mathematical Stupor . . . . . . . . . . . . . . . . . .
8.2.2 How Big is a Genome? . . . . . . . . . . . . . . . . . . .
8.2.3 The Geography of Chromosomes . . . . . . . . . . . . .
8.2.4 DNA Looping: From Chromosomes to Gene Regulation
8.2.5 PCR, DNA Melting and DNA Bubbles . . . . . . . . . .
8.3 The New World of Single Molecule Mechanics . . . . . . . . . .
8.3.1 Force-Extension Curves: A New Spectroscopy . . . . . .
8.3.2 Random Walk Models for Force-Extension Curves . . .
8.4 Proteins as Random Walks . . . . . . . . . . . . . . . . . . . .
8.4.1 Compact Random Walks and the Size of Proteins . . . .
8.4.2 Hydrophobic and Polar Residues: The HP Model . . . .
8.4.3 HP Models of Protein Folding . . . . . . . . . . . . . . .
8.5 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . .
8.6 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . .
8.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9 Electrostatics for Salty Solutions
9.1 Water as Lifes Aether . . . . . . . . . . . . . . .
9.2 The Chemistry of Water . . . . . . . . . . . . . .
9.2.1 pH and the Equilibrium Constant . . . .
9.2.2 The Charge on DNA and Proteins . . . .
9.2.3 Salt and Binding . . . . . . . . . . . . . .
9.3 Electrostatics for Salty Solutions . . . . . . . . .
9.3.1 An Electrostatics Primer . . . . . . . . .
9.3.2 The Charged Life of a Protein . . . . . .
9.3.3 The Notion of Screening: Electrostatics in
9.3.4 The Poisson-Boltzmann Equation . . . . .
9.3.5 Viruses as Charged Spheres . . . . . . . .
9.4 Summary and Conclusion . . . . . . . . . . . . .
9.5 Problems . . . . . . . . . . . . . . . . . . . . . .
9.6 Further Reading . . . . . . . . . . . . . . . . . .
9.7 References . . . . . . . . . . . . . . . . . . . . . .

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10 Beam Theory: Architecture for Cells and Skeletons

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10.1 Beams are Everywhere: From Flagella to the Cytoskeleton . . . . 496
10.2 Geometry and Energetics of Beam Deformation . . . . . . . . . . 497
10.2.1 Stretch, Bend and Twist . . . . . . . . . . . . . . . . . . . 497
10.2.2 Beam Theory and the Persistence Length: Stiffness is Relative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
10.2.3 Elasticity and Entropy: The Worm-like Chain . . . . . . . 506
10.3 The Mechanics of Transcriptional Regulation: DNA Looping Redux508

CONTENTS
10.3.1 The Lac Operon and Other Looping Systems . . . . . . .
10.3.2 Energetics of DNA Looping . . . . . . . . . . . . . . . . .
10.3.3 Putting it all together: The J Factor . . . . . . . . . . . .
10.4 DNA Packing: From Viruses to Eukaryotes . . . . . . . . . . . .
10.4.1 The Problem of Viral DNA Packing . . . . . . . . . . . .
10.4.2 Constructing the Nucleosome . . . . . . . . . . . . . . . .
10.4.3 Equilibrium Accessibility of Nucleosomal DNA . . . . . .
10.5 The Cytoskeleton and Beam Theory . . . . . . . . . . . . . . . .
10.5.1 The Cellular Interior: A Structural Perspective . . . . . .
10.5.2 Stiffness of Cytoskeletal Filaments . . . . . . . . . . . . .
10.5.3 Cytoskeletal Buckling . . . . . . . . . . . . . . . . . . . .
10.5.4 Estimate of the Buckling Force . . . . . . . . . . . . . . .
10.6 Beams and Biotechnology . . . . . . . . . . . . . . . . . . . . . .
10.6.1 Biofunctionalized Cantilevers and Molecular Recognition .
10.7 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .
10.8 Appendix: The Mathematics of the Worm-Like Chain . . . . . .
10.9 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.10Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.11References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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11 Biological Membranes: Life in Two Dimensions

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11.1 The Nature of Biological Membranes . . . . . . . . . . . . . . . . 561
11.1.1 Cells and Membranes . . . . . . . . . . . . . . . . . . . . 561
11.1.2 The Chemistry and Shape of Lipids . . . . . . . . . . . . 566
11.1.3 The Liveliness of Membranes . . . . . . . . . . . . . . . . 570
11.2 On the Springiness of Membranes . . . . . . . . . . . . . . . . . . 576
11.2.1 An Interlude on Membrane Geometry . . . . . . . . . . . 577
11.2.2 Free Energy of Membrane Deformation . . . . . . . . . . 582
11.3 Structure, Energetics and Function of Vesicles . . . . . . . . . . . 587
11.3.1 Measuring Membrane Stiffness . . . . . . . . . . . . . . . 587
11.3.2 Membrane Pulling . . . . . . . . . . . . . . . . . . . . . . 591
11.3.3 Vesicles in Cells . . . . . . . . . . . . . . . . . . . . . . . . 595
11.3.4 Fusion and Fission . . . . . . . . . . . . . . . . . . . . . . 602
11.4 Membranes and Shape . . . . . . . . . . . . . . . . . . . . . . . . 602
11.4.1 The Shapes of Organelles . . . . . . . . . . . . . . . . . . 604
11.4.2 The Shapes of Cells . . . . . . . . . . . . . . . . . . . . . 607
11.5 The Active Membrane . . . . . . . . . . . . . . . . . . . . . . . . 611
11.5.1 Mechanosensitive Ion Channels and Membrane Elasticity 611
11.5.2 Elastic Deformations of Membranes Produced by Proteins 611
11.5.3 One-Dimensional Solution for MscL . . . . . . . . . . . . 614
11.6 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . 621
11.7 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
11.8 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
11.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629

CONTENTS

III

Life in Motion

633

12 The Mathematics of Water

12.1 Putting Water in its Place . . . . . . . . . . . . . . . . . . . . . .
12.2 Hydrodynamics of Water and Other Fluids . . . . . . . . . . . .
12.2.1 Water as a continuum . . . . . . . . . . . . . . . . . . . .
12.2.2 What Can Newton Tell Us? . . . . . . . . . . . . . . . . .
12.2.3 F = ma For Fluids . . . . . . . . . . . . . . . . . . . . . .
12.2.4 The Newtonian Fluid and the Navier-Stokes Equations . .
12.3 The River Within: Fluid Dynamics of Blood . . . . . . . . . . .
12.3.1 Boats in the River: Leukocyte Rolling and Adhesion . . .
12.4 The Low-Reynolds Number World . . . . . . . . . . . . . . . . .
12.4.1 Stokes Flow: Consider a Spherical Bacterium . . . . . . .
12.4.2 Stokes Drag in Single Molecule Experiments . . . . . . . .
12.4.3 Dissipative Time Scales and the Reynolds Number . . . .
12.4.4 Fish Gotta Swim, Birds Gotta Fly and Bacteria Gotta
Swim Too . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.4.5 Centrifugation and Sedimentation: Spin it Down . . . . .
12.5 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .
12.6 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.7 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

635
635
636
636
637
639
643
644
647
648
648
653
654

13 A Statistical View of Biological Dynamics

13.1 Diffusion in the Cell . . . . . . . . . . . . . . . . . . . . . . . . .
13.1.1 Active versus Passive Transport . . . . . . . . . . . . . . .
13.1.2 Biological Distances Measured in Diffusion Times . . . . .
13.1.3 Random Walk Redux . . . . . . . . . . . . . . . . . . . .
13.2 Concentration Fields and Diffusive Dynamics . . . . . . . . . . .
13.2.1 Diffusion by Summing Over Microtrajectories . . . . . . .
13.2.2 Solutions and properties of the diffusion equation . . . . .
13.2.3 FRAP and FCS . . . . . . . . . . . . . . . . . . . . . . .
13.2.4 Drunks on a Hill: The Smoluchowski Equation . . . . . .
13.2.5 The Einstein Relation . . . . . . . . . . . . . . . . . . . .
13.3 Diffusion to capture . . . . . . . . . . . . . . . . . . . . . . . . .
13.3.1 Modeling the cell signaling problem . . . . . . . . . . . .
13.3.2 A Universal Rate for Diffusion-Limited Chemical Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13.4 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .
13.5 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13.6 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . .
13.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

669
669
670
672
676
678
682
689
690
695
696
698
699

656
659
663
663
666
668

704
705
706
707
709

10

CONTENTS

14 Life in Crowded and Disordered Environments

14.1 Crowding, Linkage and Entanglement . . . . . . . . . . . . . . .
14.1.1 The Cell is Crowded . . . . . . . . . . . . . . . . . . . . .
14.1.2 Macromolecular Networks: The Cytoskeleton and Beyond
14.1.3 Crowding on Membranes . . . . . . . . . . . . . . . . . .
14.1.4 Consequences of Crowding . . . . . . . . . . . . . . . . . .
14.2 Equilibria in Crowded Environments . . . . . . . . . . . . . . . .
14.2.1 Crowding and binding . . . . . . . . . . . . . . . . . . . .
14.2.2 Osmotic Pressures in Crowded Solutions . . . . . . . . . .
14.2.3 Depletion Forces: Order from Disorder . . . . . . . . . . .
14.2.4 Excluded Volume and Polymers . . . . . . . . . . . . . . .
14.3 Crowded Dynamics . . . . . . . . . . . . . . . . . . . . . . . . . .
14.3.1 Crowding and Reaction Rates . . . . . . . . . . . . . . . .
14.3.2 Diffusion in Crowded Environments . . . . . . . . . . . .
14.4 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .
14.5 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.6 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

711
711
712
713
715
717
721
721
725
729
736
740
740
742
745
745
747
748

15 Rate Equations and Dynamics in the Cell

15.1 Biological Statistical Dynamics: A First Look . . . . . . . . . . .
15.1.1 Cells as Chemical Factories . . . . . . . . . . . . . . . . .
15.1.2 Dynamics of the Cytoskeleton . . . . . . . . . . . . . . . .
15.2 A Chemical Picture of Biological Dynamics . . . . . . . . . . . .
15.2.1 The Rate Equation Paradigm . . . . . . . . . . . . . . . .
15.2.2 All Good Things Must End . . . . . . . . . . . . . . . . .
15.2.3 A Single Molecule View of Degradation: Statistical Mechanics Over Trajectories . . . . . . . . . . . . . . . . . .
15.2.4 Bimolecular Reactions . . . . . . . . . . . . . . . . . . . .
15.2.5 Dynamics of Ion Channels as a Case Study . . . . . . . .
15.2.6 Rapid equilibrium . . . . . . . . . . . . . . . . . . . . . .
15.2.7 Michaelis-Menten and Enzyme Kinetics . . . . . . . . . .
15.3 The Cytoskeleton is Always Under Construction . . . . . . . . .
15.3.1 The Eukaryotic Cytoskeleton . . . . . . . . . . . . . . . .
15.3.2 The Curious Case of the Bacterial Cytoskeleton . . . . . .
15.4 Simple Models of Cytoskeletal Polymerization . . . . . . . . . . .
15.4.1 The Equilibrium Polymer . . . . . . . . . . . . . . . . . .
15.4.2 Rate Equation Description of Cytoskeletal Polymerization
15.4.3 Nucleotide Hydrolysis and Cytoskeletal Polymerization .
15.4.4 Dynamic Instability: A Toy Model of the Cap . . . . . . .
15.5 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .
15.6 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15.7 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . .
15.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

751
751
752
753
758
758
760
762
768
771
776
783
786
788
789
792
795
800
806
808
814
815
818
819

CONTENTS
16 Dynamics of Molecular Motors
16.1 The Dynamics of Molecular Motors: Life in the Noisy Lane . .
16.1.1 Translational Motors: Beating the Diffusive Speed Limit
16.1.2 Rotary Motors . . . . . . . . . . . . . . . . . . . . . . .
16.1.3 Polymerization Motors: Pushing By Growing . . . . . .
16.1.4 Translocation Motors: Pushing by Pulling . . . . . . . .
16.2 Rectified Brownian Motion and Molecular Motors . . . . . . . .
16.2.1 The Random Walk Yet Again . . . . . . . . . . . . . . .
16.2.2 The One-state Model . . . . . . . . . . . . . . . . . . .
16.2.3 Motor stepping from a free energy perspective . . . . .
16.2.4 The Two-state model . . . . . . . . . . . . . . . . . . .
16.2.5 More General Motor Models . . . . . . . . . . . . . . .
16.2.6 Coordination of Motor Protein Activity . . . . . . . . .
16.2.7 Rotary Motors . . . . . . . . . . . . . . . . . . . . . . .
16.3 Polymerization and Translocation as Motor Action . . . . . . .
16.3.1 The Polymerization Ratchet . . . . . . . . . . . . . . . .
16.3.2 Force Generation by Growth . . . . . . . . . . . . . . .
16.3.3 The Translocation Ratchet . . . . . . . . . . . . . . . .
16.4 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . .
16.5 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16.6 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . .
16.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

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17 Biological Electricity and the Hodgkin-Huxley Model

17.1 The Role of Electricity in Cells . . . . . . . . . . . . . . . . . . .
17.2 The Charge State of the Cell . . . . . . . . . . . . . . . . . . . .
17.2.1 The Electrical Status of Cells and Their Membranes . . .
17.2.2 Electrochemical Equilibrium and the Nernst Equation . .
17.3 Membrane Permeability: Pumps and Channels . . . . . . . . . .
17.3.1 Ion Channels and Membrane Permeability . . . . . . . . .
17.3.2 Maintaining a Nonequilibrium Charge State . . . . . . . .
17.4 The Action Potential . . . . . . . . . . . . . . . . . . . . . . . . .
17.4.1 Membrane Depolarization: The Membrane as a Bistable
Switch . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17.4.2 The Cable Equation . . . . . . . . . . . . . . . . . . . . .
17.4.3 Depolarization waves . . . . . . . . . . . . . . . . . . . . .
17.4.4 Spikes . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17.4.5 Hodgkin-Huxley and Membrane Transport . . . . . . . .
17.5 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .
17.6 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17.7 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . .
17.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

821
821
824
835
839
841
843
844
847
856
861
868
869
875
878
878
887
890
895
895
898
900
903
903
905
905
905
908
910
915
918
918
931
933
937
939
941
941
944
945

12

IV

CONTENTS

The Meaning of Life

18 Sequences, Specificity and Evolution

18.1 Biological Information . . . . . . . . . . . . . . . . . . . . . . . .
18.1.1 Why Sequences? . . . . . . . . . . . . . . . . . . . . . . .
18.1.2 Genomes and Sequences by the Numbers . . . . . . . . .
18.2 Sequence Alignment and Homology . . . . . . . . . . . . . . . . .
18.2.1 The HP Model as a Coarse-Grained Model for Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18.2.2 Scoring Success . . . . . . . . . . . . . . . . . . . . . . . .
18.3 Sequences and Evolution . . . . . . . . . . . . . . . . . . . . . . .
18.3.1 Evolution by the Numbers: Hemoglobin as a Case Study
in Sequence Alignment . . . . . . . . . . . . . . . . . . . .
18.3.2 Evolution and Drug Resistance . . . . . . . . . . . . . . .
18.3.3 The Evolution of Viruses . . . . . . . . . . . . . . . . . .
18.3.4 Phylogenetic Trees . . . . . . . . . . . . . . . . . . . . . .
18.4 The Molecular Basis of Fidelity . . . . . . . . . . . . . . . . . . .
18.4.1 Keeping it Specific: Beating Thermodynamic Specificity .
18.5 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .
18.6 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18.7 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . .
18.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

947
949
950
951
952
954
960
962
973
975
979
982
984
987
988
995
996
1000
1002

19 Network Organization in Space and Time

1005
19.1 Chemical and Informational Organization in the Cell . . . . . . . 1005
19.2 Genetic Networks: Doing the Right Thing at the Right Time . . 1012
19.2.1 The Molecular Implementation of Regulation: Promoters,
Activators and Repressors . . . . . . . . . . . . . . . . . . 1013
19.2.2 The Mathematics of Recruitment and Rejection . . . . . . 1016
19.2.3 Transcriptional Regulation By the Numbers: Binding Energies and Equilibrium Constants . . . . . . . . . . . . . . 1026
19.2.4 A Simple Statistical Mechanics Model of Positive and
Negative Regulation . . . . . . . . . . . . . . . . . . . . . 1027
19.2.5 The lac Operon . . . . . . . . . . . . . . . . . . . . . . . . 1028
19.3 Regulatory Dynamics . . . . . . . . . . . . . . . . . . . . . . . . 1038
19.3.1 The Dynamics of RNA Polymerase and the Promoter . . 1038
19.3.2 Genetic Switches: Natural and Synthetic . . . . . . . . . 1039
19.3.3 Genetic Networks That Oscillate: The Repressilator . . . 1045
19.3.4 Putting Space in the Model: Reaction-Diffusion Models . 1051
19.4 Cellular Fast Response: Signaling . . . . . . . . . . . . . . . . . . 1052
19.4.1 Bacterial Chemotaxis . . . . . . . . . . . . . . . . . . . . 1053
19.4.2 Biochemistry on a Leash . . . . . . . . . . . . . . . . . . . 1058
19.5 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . 1065
19.6 Appendix: Stability Analysis for the Genetic Switch . . . . . . . 1066
19.7 Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
19.8 Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072

CONTENTS

13

19.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073

20 Whither Physical Biology?
20.1 Quantitative Data Demands Quantitative Models
20.2 Wrong Again . . . . . . . . . . . . . . . . . . . .
20.3 Order-of-Magnitude Biology and Beyond . . . . .
20.4 Difficulties on Theory . . . . . . . . . . . . . .
20.5 A Charge to the Reader . . . . . . . . . . . . . .
20.6 Further Reading . . . . . . . . . . . . . . . . . .
20.7 References . . . . . . . . . . . . . . . . . . . . . .

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1075
. 1075
. 1079
. 1080
. 1081
. 1086
. 1087
. 1088